Personal Practice
Neonatal Sepsis
N.B. Mathur
Definitions and Current Concepts of
Terminology
Neonatal sepsis is a clinical syndrome
characterized by systemic signs of infection
and accompanied by bacteremia in the first
month of life(l). Once bacteria gain access
to the bloodstream, mechanisms are
activated by the host for their elimination.
Usually the bacteria are efficiently cleared
by the monocyte-macrophage system after
opsonization by antibody and complement.
Sometimes, however, a systemic
inflammatory response syndrome is
established and can progress independently
of the original infection (2). In many
patients with sepsis, it is difficult to
document a bacterial cause. The term
systemic inflammatory response syndrome
includes several stages of infection from
sepsis, sepsis syndrome and early septic
shock to refractory septic shock, which can
eventuate in multiple organ dysfunction
and death (3). Fig. 1 depicts the clinical
criteria for the diagnosis of these conditions
(4).
Sepsis is considered when there is a
systemic response to possible infection.
Evidence of bacteremia or an infectious
focus
From the Department of Pediatrics, Maulana Azad
Medical College and Lok Nayak Hospital, Neiv
Delhi 110 002.
Reprint requests: Dr. N.B. Mathur, 187, Rouse
Avenue, Deen Dayal Upadhyaya Marg, New
Delhi 110 002.
INDIAN PEDIATRICS
is not required. When a pathogen is
recovered from blood cultures or identified
by other means, sepsis caused by that
organism is the preferred term. It is felt that
the term septicemia should be abandoned
to avoid confusion. Septic shock ensues
when systolic blood pressure drops below
the 5th percentile or peripheral
hypoperfusion (poor capillary refill) is
present. If shock responds promptly to
parenteral fluid administration and
pharmacologic treatment, it is defined as
early septic shock (hyperdynamic or warm
phase of septic shock). Refractory septic
shock is hypodynamic or cold phase of
septic shock, which persists beyond 1 hour
inspite of adequate treatment.
Current Concepts in Pathophysiology
The systemic inflammatory response
depends on the host's ability to recognize
foreign substances. Although this response
facilitates microbial clearance, the host
must pay the price of some tissue damage
to achieve this goal. Fig. 2 depicts a
schematic outline of the putative
pathophysiologic events in the septic
process (4).
Earlier it was believed that the bacteria
or their cell wall components (endotoxins
of Gram-negative organisms and
lipoteichoic acid-peptidoglycan complex of
Gram-positive bacteria) were largely
responsible for the direct toxic effects on
tissues. Recent research indicates that the
physiologic effects generated by bacterial
infections are largely mediated by
interaction of pro-inflammatory cytokines
activated in response to the presence of
microbial components within the vascular
compartment(5-ll). The prominent among
these cytokines are tumor necrosis factor
(TNF)
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Fig. 1. Proposed terminology of the septic process (systemic inflammatory response syndrome). The risk of
dying increases as one moves down the algorithm. Adapted from Saez-Llorens and McCracken GH(4)
and interleukin (IL)-l, which are rapidly
produced by macrophages, endothelial
cells and many other cellular elements on
exposure to bacterial products. Adminis-
tration of these cytokines has induced fe-
ver, acute phase changes, hypotension
and endothelial injury, alterations similar
to those observed after endotoxin or
bacterial inoculation(12-16). Several
studies have demonstrated elevated TNF
level in adults with bacterial sepsis which
correlated with mortality rates(17,18).
Data regarding plasma cytokines in
children with sepsis is scanty. However,
higher levels of IL-1, IL-6 and TNF have
also been observed in children(14-
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20) and neonates(21-23) with sepsis and
found to correlate with fatality. A
number of other mediators like IL-8,
platelet activating factor, interferon gam-
ma, macrophage derived proteins,
arachidonic acid metabolites and some
still unidentified substances also amplify
the systemic inflammatory response.
Two components of complement C3a
and C5a are cationic peptides with
anaphylatoxin activities capable of
provoking release of histamine from mast
cells and basophils, contraction of
smooth muscle and increased capillary
permeability, which can aggravate
hypotension in sepsis(24).
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DEATH
Fig. 2. Hypothetical pathophysiology of the septic process. Adapted from Saez-Llorens and McCracken GH(4).
The intrinsic coagulation pathway may be
activated by a direct interaction between
endotoxin and coagulation factor XII.
Endotoxins can induce the release of the
tissue factor by monocytes and endothelial
cells directly or through cytokines. Thus
factor VII and the extrinsic coagulation
pathway is also activated, leading to the
development of disseminated intravascular
coagulation. Factor XII also stimulates the
conversion of prekalikrein to kallikrein and
the subsequent conversion of kininogen to
bradykinin which is a potent vasodilator(25).
Polymorphonuclear leukocytosis is
frequently seen with sepsis. The release of
neutrophils from marrow reserves is induced
by endotoxin, cytokines, complement or
granulocyte-colony stimulating factors
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(26,27). Neutropenia may occur due to
inadequate marrow function, increased
destruction or consumption of circulating
neutrophils or margination and attachment of
neutrophils to endothelial cells. Bone marrow
granulocyte reserve pool is small in neonates
and neutropenia is associated with a high
fatality.
Neutrophils initiate phagocytosis and
microbial killing by degranulation and
release of several proteolytic enzymes and
toxic oxygen radicals, a process that can also
cause damage to nearby tissues.
Additionally, neutrophil induced digestion of
surrounding tissue contributes to separation
of tight endothelial cell junctions and
development of capillary leak syndrome and
septic shock.
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Bacteriology
The microbial etiology of neonatal
sepsis is variable and often changes
temporally. Group B streptococcus is a
common cause of neonatal sepsis in the
West but infrequent in India and other
tropical countries. In Indian studies, Gram
negative organisms have been more
frequently responsible for sepsis (65-85%)
as compared to Gram positive organisms.
Commonly found organisms are Klebsiella,
E. coli, Pseudomonas, Staph. aureus and
coagulase negative Staphylococcus.
Enterobacter, Citrobacter, Proteus
mirabilis and Serratia, are also seen.
Group B streptococcus is an infrequent
cause.
Extent of Problem
Neonatal sepsis continues to be a major
cause of neonatal mortality in India
accounting for one-fourth to nearly half of
neonatal deaths (28-30). Fatality due to
sepsis ranges between 40 and 65% (31-34).
Preterm and small for gestational age in-
fants are more prone to develop sepsis than
term and appropriate for gestational age
infants.
In the United States, sepsis (positive
blood or cerebrospinal fluid culture)
accounts for 30% of the neonatal
deaths(35) and the incidence of neonatal
sepsis among all live births ranges from 2-
8 per 1000(35,36). The overall fatality in
neonatal sepsis in the USA remains at
25%. In addition, nearly 50% of infants die
when there is a fulminant onset of sepsis
within the first day of life and 80-90% of
neutropenic infants may die of sepsis when
there is depletion of the bone marrow
neutrophil storage pool(35). The mortality
rate is close to 100% in infants with early
onset Group B streptococcal sepsis
weighing less than 1500 g at birth
compared to a rate of 20% in infants
weighing more than 2500 g at birth(37).
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The risk of fatality is expected to increase
with progressive stages of systemic
inflammatory response syndrome and the
fatality in septic shock in adult patients is 80%.
Correlation of fatality with the stage of the
systemic inflammatory response syndrome has
not been studied in neonates. In a recent
study(38), designed to evaluate risk factors at
admission in fatal sepsis in neonates brought to
a referral neonatal unit, we observed that the
independent factors significantly associated
with death were neutropenia, metabolic
acidosis, increased prothrombin time and
refractory septic shock (Odd's ratio 0.9, 1.14,
1.04 and 11.82, respectively). Recognition of
these factors at admission of septic neonates to
referral units are important for targeting them
for intensive care and immunotherapy.
Investigatory Approach
It is important to note that infants with
bacterial sepsis may have negative blood
cultures. The investigatory approach is
summarized in Table I.
Management
The important aspects of management
include: (i) Administration of parenteral
fluids, vasoactive agents and oxygen to
ensure perfusion and oxygenation of vital
tissues; (ii) Antimicrobial agents and early
drainage or removal of purulent foci for
bacterial eradication; and (iii)
Immunotherapy.
Hemodynamic Stability and Tissue
Oxygenation
Management of fluid and electrolyte
balance is vital in the treatment of sepsis,
particularly when shock is present. Every
effort to enhance oxygen delivery to the
tissues must be made. The increased work of
breathing in patients with sepsis syndrome
and septic shock can increase tissue oxygen
consumption. This problem can be overcome
by using assisted ventilation. Extremes of
body temperature should be avoided
because they increase oxygen
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TABLE—I Investigatory Approach to
Neonatal Sepsis.
Evidence for infection
Culture from blood, CSF, urine
Demonstration of a micro-organism in
tissue, fluid or buffly coat smear, using
Gram stain or Acridine orange stain,
Antigen detection (CSF).
Evidence for inflammation
Leukocytosis, increased immature/total
neutrophil ratio, neutropenia.
Pleocytosis in CSF, synovial or pleural
fluid.
Acute phase reactants: CRP, ESR.
Cytokines: IL-6
Evidence for multiorgan dysfunction
Metabolic acidosis: pH, PCO2 Pulmonary
functions: PO2, PCO2 Renal functions:
Blood urea, creatinine Hepatic functions:
Bilirubin, SGPT, SGOT Disseminated
intravascular coagulation: Coagulation
profile, fibrin split products.
requirements(39,40).Infants in shock
require above normal oxygenation,
ventilation and circulation and
management includes supplemental
oxygen(41). Breathing support by bag and
mask ventilation should be started unless
respiration is judged adequate. Slow and
shallow respirations are not sufficient in
the presence of shock. Frank shock
constitutes an indication for controlled
assisted ventilation(42).
Common errors in treating shock
include the use of a diluted fluid, use of too
little fluid or slow administration of fluid.
Only those fluids at least isotonic to serum
have a role in shock. Isotonic fluids like
lactated Ringer's solution and 0.9% normal
saline must fill the entire extracellular fluid
compartment. More dilute solutions are
shared with the intracellular space as well.
Bolus therapy is usually given in aliquots
of 20 ml/kg rapidly (in 4-5 minutes) (43).
INDIAN PEDIATRICS
If two boluses 'of crystalloid solutions fail,
colloid solutions (plasma, albumin or
dextran) may be useful.
Dopamine is the initial inotropic agent
of choice in septic shock because of its
beta adrenergic effects on the myocardium,
alpha adrenergic effects on the peripheral
vasculature and dopaminergic effects on
renal and splanchnic vessels. If myocardial
function is decreased and systemic
vascular resistance is elevated, the
combined use of dobutamine and low
doses of dopamine can be helpful.
Electrolyte abnormalities, metabolic
acidosis and decreased level of calcium
phosphate and glucose may be present and
should be corrected to achieve optimal
myocardial function. Guidelines for the
management of septic shock are
summarized in Fig. 3.
Bacterial Eradication
Prompt administration of antibiotics
empirically is important. The choice of
initial antibiotics depends on the likely
etiologic agent, the microbial susceptibility
patterns in the nursery, tissue penetration,
toxicity, cost and availability of the
antibiotic.
The traditional Western
recommendation for initial antibiotics in
neonatal sepsis is a combination of
ampicillin with an aminoglycoside and
may be used in respiratory infections and
when sepsis is suspected. However,
resistance to ampicillin is frequently
observed (31). Third generation
caphalosporinss (cefotaxime, ceftazidime)
are more useful in Gram negative
infections commonly encountered in India.
They are not effective against Listeria and
Enterococcus. However, these
pathogens have not been reported
commonly from India. Aminoglycosides
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Fig. 3. Guidelines for the management of septic shock.
continue to remain useful against E. coli,
Klebsiella and Pseudomonas
The choice of antibiotics should be re-
evaluated when results of cultures and
susceptibility tests become available and if
the patient does not respond clinically.
Ciprofloxacin is being used in life
threatening sepsis when the organism
isolated is resistant to all the other available
antibiotics. The duration of therapy depends
on the initial response to the antibiotics but
should be 7 to 10 days in most infants with
sepsis. The minimal duration of therapy is 21
days for infants with meningitis caused by
Gram negative enteric bacilli. Any purulent
foci or abscesses should be drained.
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Exchange Transfusion
Theoretic and documented benefits of
exchange transfusions in neonatal sepsis
include the following(44-50): (i) Increase in
circulating levels of C3 immunoglobulins,
particularly IgM and IgA which may enhance
defense mechanisms; (ii) Removal of
bacteria and bacterial toxins; (iii)
Improvement in the opsonic activity against
the offending organism; (iv) Correction
of neutropenia with enhanced neutrophil
function; (v) Improvement in perfusion and
tissue oxygenation; (vi) Decrease in
hemorrhagic complications by correcting
the platelet count and plasma coagulation sys
tern and removing fibrin degradation
products; and (vii) Resolution of sclerema
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A survey of the outcome of the published controlled trial in septic neonates with
reports of exchange transfusion in neonatal neutropenia recorded significant
sepsis shows that the survival in nine non- improvement in neutrophil count and func-
randomized predominantly retrospective tion. The survival was 65% in the
trials was 62% for infants receiving exchange group and 30% in controls
exchange transfusions and 38% for those in (p=0.7)(48).
the control group(51-59). Similarly, the
In summary, exchange transfusion in
survival of septic neonates in six
neonatal sepsis is appealing, particularly in
uncontrolled trials of exchange
the developing world because it is more
transfusions was also 62% (46,58,60-63)
readily available and affordable than
(Table II). Unfortunately none of these
granulocyte transfusion and IV
studies were randomized and in many
immunoglobulins. Unfortunately, its
instances the controls were not from
effectiveness has not been adequately
simultaneous years. In addition to design
evaluated. We prefer to do exchange
problems, patient selection and care varied
transfusion in neonatal sepsis associated
remarkably (35). A recent randomized

TABLE II - Survival of Septic Infants in Relation to Exchange Transfusion

Authors Year Survival n (%)
Transfused Not transfused

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with neutropenia, sclerema, earliest evidence Other Therapeutic Agents

of disseminated intravascu-lar coagulation
and metabolic acidosis (pH <7.2). Newer agents being evaluated include
human monoclonal antibodies, fibronectin,
granulocyte-macrophage colony
Granulocyte Transfusion in Neonatal Sepsis
stimulating factor/ vitamin C, levamisole
and pentoxifylline (2,77). In the future,
This adjunct to therapy of neonatal sepsis agents manipulating the neonate's own
may be useful, particularly in defense system are likely to play a major
neutropenia(64). Few studies of transfusion role in the management of severe neonatal
of adult granulocytes have shown promising sepsis.
results(65-71). However, they differ in study
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NOTES AND NEWS

EXHIBITION ON CLINICAL PEDIATRICS

An exhibition of photographs of clinical pediatric cases is being organized during the

National Conference of IAP at Ahmedabad. Two copies of photographic prints of up to post
card size (color or B&W) are solicited from IAP members and Post Graduate students from
their collection along with a brief summary of the case. Contributions will be gratefully
acknowledged. Kindly correspond with: Dr. Hemant A. Joshi, Joshi Children Hospital, Opp.
Railway Station, Virar-401 303 (Maharashtra), Tel: 0252-382709 or Dr. Niranjan
Shendurnikar, B/142, Jagannath Puram, Near Lalbaug Crossing, Baroda 390 001, (Gujarat)
Tel.: 0265-446446.

IMMUNIZATION RECORD

Newer vaccines would be introduced from time to time, and Immunization Schedules
may also need some changes from time to time. An 'Immunization record' has been designed
to accommodate all such changes. The booklet also has some essential information for the
parents. The price of the booklet is Rs. 10/-. For Doctors a packet of 25 copies is available
for Rs. 200/- and a packet of 55 copies for Rs. 400/-. The charges include postage. The
amount can be sent by a Demand Draft or Money Order to Dr. Yash Paul, A-C-4, Gayatri
Sadan, Jai Singh Highway, Bani Park, Jaipur 302 016.

INDIAN PEDIATRICS 674 VOLUME 33- AUGUST 1996